PROJECT SUMMARY Mekanistic Therapeutics seeks to design, discover, and develop anti-cancer agents that selectively inhibit multiple oncogenic pathways. Its lead agent MTX-211 was discovered in collaboration with the Leopold laboratory at University of Michigan. MTX-211 is a novel kinase inhibitor showing early promise for its therapeutic potential against solid cancers refractory to current treatment options. The goal of this STTR application is to demonstrate the scientific merit and therapeutic feasibility of developing MTX-211 to treat KRAS mutant colorectal cancers. Every year >130,000 new patients are diagnosed with colorectal cancer. At the time of diagnosis, approximately 20% of these patients present with metastatic disease. Patients diagnosed with metastatic colorectal cancer (mCRC) have a very poor prognosis, with 5 year survival rates of less than 15%. A small percentage of these patients respond to first line treatment with EGFR monoclonal antibodies (cetuximab or panitumumab). However, these agents confer no benefit to the 50% of the mCRC patient population whose tumors harbor a mutation in the KRAS oncogene. Currently, there are no approved treatments for mCRC patients with activating mutations in KRAS. MTX-211 is a first-in-class dual inhibitor of PI3K and EGFR kinases with demonstrated in vivo anticancer activity against multiple KRAS mutant colorectal tumors. MTX-211 is innovative because it attacks KRAS oncogenic signaling using two orthogonal mechanisms, serving as a combination approach in a single molecule. Unlike previously reported dual receptor tyrosine and lipid kinase inhibitors, MTX-211 is highly selective for EGFR and PI3K family members. As such, it has limited off-target toxicity and a broad therapeutic window. The long-term goal of this proposal is to improve the clinical outcome of patients diagnosed with metastatic colorectal cancer with activating mutations in KRAS. In Specific Aim 1, we will scale up synthesis of MTX-211 at the 20 gram scale to generate sufficient materials for Specific Aim 2. In Specific Aim 2, we propose to evaluate the efficacy of MTX-211 against six KRAS mutant CRC PDX models. The histology of all six models has been confirmed to recapitulate that of the original patient specimen and all have been fully profiled by whole exome sequencing. Successful demonstration of an overall response rate of 30% in this pilot trial would be followed by a Phase II plan to conduct an expanded mouse trial of MTX-211 against a broader CRC PDX panel. The expected outcome of a precision medicine-focused Phase II proposal would be a clearly defined patient enrichment strategy and identified prognostic markers that track therapeutic outcome in response to dual inhibition of EGFR/PI3K pathways with MTX-211. Combined Phase I and II applications will provide pivotal data necessary to justify completing an investigative new drug (IND) package.